PROJECT SUMMARY Chemotherapy-induced peripheral neuropathy (CIPN) is a debilitating condition that afflicts 70% of cancer patients undergoing chemotherapy and limits the dose and duration of treatment. Symptoms range from sensory loss to painful neuropathy and are accompanied by electrophysiological and structural indices of nerve damage. The American Society of Clinical Oncology currently makes no recommendations for the prevention or reversal of CIPN and provides only a moderate recommendation for symptomatic pain relief. CIPN is therefore a major unmet clinical concern. WinSanTor's founders have discovered a novel homeostatic mechanism in peripheral neurons that restrains axonal growth via regulation of mitochondrial energy supply. Manipulation of this endogenous mechanism can be exploited to improve energy supply to neurons undergoing toxic or metabolic stress, thereby supporting both neuroprotection and recovery from established injury. We have recently reported that the key neuronal receptor regulating this mechanism is the muscarinic acetylcholine type 1 receptor (M1R) and that M1R antagonists increase neuronal respiratory capacity and drive neurite outgrowth. Additionally, in vivo studies demonstrated that the selective M1R antagonist pirenzepine, which has been used worldwide for 30+ years to treat gastric ulcers, prevented and/or reversed multiple indices of neuropathy in rodent models of toxic and metabolic injury. Encouraging preliminary studies supported by a Phase I STTR award demonstrate that pirenzpine both prevents and reverses indices of neuropathic pain and degenerative neuropathy in models of paclitaxel-induced CIPN without impeding the tumoricidal properties of paclitaxel. The goals of this Phase II STTR project are to define the optimal therapeutic regimen for pirenzepine against paclitaxel-induced CIPN (Aim 1), to establish the broadest market for this approach by extending studies to CIPN induced by three distinct chemotherapeutics (Aim 2) and to complete necessary IND-enabling studies in preparation for clinical trials (Aim 3) en route to advancing pirenzepine as a first in-class therapy against CIPN.